the Air Vent

Because the world needs another opinion

Strong Data Again

Posted by Jeff Id on March 30, 2020

I’m not sure why so many of one political party want to say that hydroxychloroquine azythromycin is only anecdotally effective.   Maybe they don’t know what that word means.

Anyway, here is another strong study but the only control subjects are the rest of the entire planet so maybe that’s not enough.

 

 

Very, very angry at our mindless fascist authoritarian Michigan governor for banning the use of these drugs.  We deserve the right to try.


25 Responses to “Strong Data Again”

  1. amac78 said

    Jeff, if as a graduate student I had reviewed the Philippe Gautret et al. paper (available here as #2), I would have said it was a crummy study. However. That would be judging it by “normal” standards, such as expecting such an important finding to be done as a Randomized Clinical Trial, with controls carefully selected to match those getting the Experimental treatment.

    In one of his interviews last week (in French, and I forget which one), Dr. Raoult explained that he would not do this, because he considers it to be unethical under the circumstances. He is a physician treating sick patients, and he considers it his duty to treat them as best he can — and he believes that hydroxychloroquine and azithromycin is by far the most effective treatment for them. Given that — how could anybody expect him to act otherwise?

    In some news articles, I’ve seen him portrayed as a cowboy, or washed-up hippie, or a peddler of phony elixers. I checked his publication record, he’s a genuine physician-scientist who’s been studying infectious diseases, mostly tropical, for decades.

    Like you, I am very hopeful that this combination therapy can be effective — not in every situation, but to help many infected patients. And possibly as a prophylaxis for health care workers. Proof will only come when other doctors reproduce Dr. Raoult’s work. If it is as effective as it seems, they, too, will be challenged to build a gold-standard RCT in the midst of a pandemic.

    Fingers crossed.

    • Jeff Id said

      The in-vitro studies at WUWT confirm that the concentration of the hydroxycloroquine at the cell walls determines whether the drug will be effective. The study which went for only 5 days and failed was stupidly performed. They didn’t even attempt to match the in-vitro successful results but instead ran too low of a dosage of the drug. The french doc understood this from the beginning and in the first study, gave rather high doses including a starting bolus to get the concentrations high enough very quickly. This stuff is working very, very well when used correctly. If you or your family ends up being prescribed this drug, make sure you do your math and insist that the doctor give the same levels as the French study. MD’s aren’t paying close enough attention to the literature to understand these minutia – as evidenced by the failed study.

      Belgium has it as a standard procedure, unfortunately combined with other potential treatments that have much less data: https://epidemio.wiv-isp.be/ID/Documents/Covid19/COVID-19_InterimGuidelines_Treatment_ENG.pdf

    • RB said

      The publisher’s statement today disavowing the Gautret et al. paper seem to be an endorsement of the objections outlined in this reply to the paper.

      “Statistical evidence for the positive effect model ranged from strong for the original data, to moderate when including patients who deteriorated, to anecdotal when excluding untested patients, and to anecdotal negative evidence if untested patients were assumed positive.”

      • Jeff Id said

        That reanalysis isn’t very good. Some of the negative assumptions and the focus on them seem a bit contrived. Complaining about the wide range of possibilities where most of the range is in the positive result range is a little silly. It’s become a political game so I trust none of this stuff.

        I’m still waiting for the good ones to arrive, but the in-vitro studies appear very solid so I have high confidence still that we will see good news from them.

  2. RB said

    If something shows potential, doctors are going to try it. Why politicize it? There are several candidates right now and medical professionals are not going to hide it from us because of their political persuasion. For this person, they tried hcq+A, then moved on to other things as the condition didn’t improve. He’s now out of ICU and we won’t know what works either.

    • RB said

      Good luck riding out the storm. Hope those who criticized my arguments in support of the 2009 bailout here see the merits of Govt support in a crisis now.

    • Jeff Id said

      It sounds like they are using hydroxychloroquine and azytrhomycin in New Orleans across a lot of people. If the stuff works, I expect we will hear very good news soon.

    • RB said

      1st patient in NJ, a Chinese-American PA:

      “Everybody use medication too late for patients in the United States. Chinese experts suggest to use hydroxychloroquine or chloroquine right after diagnosis not when patient gets worse and virus already spread in the lung. Remdesivir may work the best before ARDS (right after 2nd Worsening chest CT)”

      • Jeff Id said

        That is starting to sound like a consistent theme.

      • RB said

        Former FDA commissioner Scott Gottlieb:
        THREAD: One piece of non-scientific evidence that would nonetheless inform discussion on hydroxychloroquine in the proposed treatment of #COVID19 would be a survey on how widely it was already being used in U.S., Italy, and some other countries, long before current debate. 1/3
        Doctors have been using it widely in U.S., often in combo with azithromycin, since very outset. They used it based on a theoretical potential for benefit, the fact that it was widely available, and a perception that side effect profile is understood so risk/reward favorable 1/2
        Anyone who believes it needs to be “made available” should be assured that it is available, and has been widely used for months all around the world. If the drug combo is working its effect is probably subtle enough that only rigorous and large scale trials will tease it out 1/3
        Ultimately to meaningfully impact outcomes in current crisis, and reduce the risk of future epidemics, we’re going to need highly active medicines. We should be focused on getting these agents with a deliberate effort to support the leading drug candidates

  3. amac78 said

    I’m not a clinician, so this is a spectator sport. In the worst way, as people’s lives hang in the balance.

    Here is a Twitter thread from front-line doc Leora Horwitz in NYC, on 3/30/20 she wrote, “Our standard protocol right now is azithro/hydroxychloroquine/zinc but I have little faith in efficacy. For the patients I really worried about (fast O2 requirement rise, high inflammatory markers) I gave tocilizumab off label. Clinical trial of sarilumab starting this week.”

    Is she faithfully replicating the protocol that Didier Raoult is using at ICH in Marseille? I don’t know. That hospital’s updated tally is 1,524 Covid-19 patients treated… with 1 fatality.

    Some solid data from St. George Hospital in Beirut, Lebanon. On Facebook (3/31/20), treating physician Eid Azar shows primary data on viral load… it decreased for each of 5 patients being treated with hydroxychloroquine and azithromycin, presumably using Raoult’s protocol.

    Hope this (or another) therapy proves out!

    • RB said

      I inserted the wrong comments. David Lat:
      ——————-
      “In these patients, a drug similar to clazakizumab showed promise as an effective treatment for PATIENTS WITH RESPIRATORY FAILURE WHO WERE LIKELY TO DIE.”

      He agreed; I got the drug (along w/tocilizumab).

      I was also given Kevzara, hydroxychloroquine plus azithromycin, and Remdesivir. Which worked? Who knows!

      I believe the only antimalarial is hydroxychloroquine (using along with the antibiotic azithromycin). Kevzara, Tocilizumab, and Clazakizumab are IL-6 inhibitors (anti-inflammatory – e.g., for rheumatoid arthritis). Remdesivir is antiviral.
      ——————-

  4. LOL@Klimate Katastrophe Kooks said

    One of the guys in my shop at work went out two weeks ago with Covid19 (he’s back now). We didn’t know at the time whether he had Covid19 or just a cold, but I told him to go ahead and cough away while I was around, because I wanted to catch the virus, get over it, get immunity and no longer be subject to all this BS going on… I’d be free to go where I wanted, when I wanted.

    I also work in an international airport, and I’m constantly touching surfaces such as air handling equipment which recirculates air in the building, and biometric devices (which everyone touches). I’ve never worn a mask nor gloves nor taken any of the usually-suggested precautions.

    So if anyone has been exposed to Covid, I was, likely multiple times.

    I got a slight tickle in the back of my throat at the beginning of this week, and felt a bit tired, but it went away the next day.

    I’ve been pre-dosing with quinine and zinc. Here’s what I researched and wrote up prior to starting the pre-dosing.

    First, we establish that chloroquine is quinine produced synthetically and altered slightly to produce a new molecule for patenting purposes. The end product in the body is still quinine. Newer molecules (such as hydroxychloroquine) decrease toxicity, allowing longer dosage schedules.

    By the 1930s Dutch plantations in Java were producing 22 million pounds of cinchona bark, or 97% of the world’s quinine production. When Japan invaded Java in 1941, natural quinine supplies dried up, necessitating mass production of synthetic derivatives. [8]

    Chloroquine is an amine acidotropic form of quinine that was synthesized in Germany by Bayer in 1934 and emerged approximately 70 years ago as an effective substitute for natural quinine [4].

    Quinine is eliminated mainly by hepatic metabolism [1]. Seven metabolites have been identified with 3-hydroxyquinine being the major metabolite [1]. Other majority metabolites are (10R)‐10,11‐dihydroxyquinine and (10S)‐10,11‐dihydroxyquinine [2].

    Quinine acts against malaria by targeting its purine nucleoside phosphorylase enzyme (PfPNP) [3], but it has other effects in the body which act against coronavirus.

    Namely, it targets angiotensin-converting enzyme 2 (ACE2) [4], interfering with sialic acid biosynthesis [4]. SARS, MERS and Covid-19 use sialic acid moieties as receptors, so quinine (and its synthetic counterparts) prevent viral attachment to cell receptors.

    Hydroxychloroquine / Chloroquine / quinine can also act on the immune system through cell signalling and regulation of pro-inflammatory cytokines. [4]

    It also acts to increase zinc uptake, which has anti-viral effects. Quinine used to be sold, prior to the FDA banning it for this use, as a treatment for leg cramps. The mechanism of action is increased uptake of zinc, calcium and magnesium by reducing hepatic metabolism of zinc [10]. Now it is recommended to directly ingest zinc, calcium and magnesium for leg cramps rather than taking quinine. [9]

    This may be why people infected with Covid-19 experience a loss of the sense of taste (and smell, since the two senses are intricately connected) [11][12]. They become acutely deficient in zinc.

    As to dosage, it generally takes 4 to 5 days to completely flush quinine from the body [5]. The consumption of 10 oz. of tonic water can result in a quinine positive urine sample for a period of up to 96 hours (4 days) after intake. [5] Approximately 20% of quinine is excreted unmetabolized [6]. It has a half-life of approximately 18 hours [6].

    Quinine in tonic water in the US is limited to 83 mg / liter [7].

    Thus, we can make a simple linear extrapolation, assuming a half-life of 18 hours and ingestion of 83 mg / day. This means that after 24 hours, approximately 27.67% of the amount from the prior day remains in the system. Thus it accumulates until the body is excreting as much as is ingested. That occurs after approximately 5 days, when the dosage varies between 124.5 mg immediately after ingestion to 41.5 mg immediately prior to the next ingestion.

    Is that enough to have a prophylactic effect?

    Well, the National Institutes of Health state that chloroquine is “a potent inhibitor of SARS coronavirus infection” [13] and since SARS binds to the same cellular receptors as Covid-19, and since chloroquine is a synthetic version of quinine, it would appear that it should work.

    Pretreatment with 0.1, 1, and 10 μM chloroquine reduced infectivity by 28%, 53%, and 100%, respectively. [13]

    The EC90 value of chloroquine against the 2019-nCoV in Vero E6 cells was 6.90 μM, which can be clinically achievable as demonstrated in the plasma of rheumatoid arthritis patients who received 500 mg administration. [14]

    Interpolating the dosage of 500 mg to 6.9 μM concentration, for a dosage of 124.5 mg daily (83 mg from tonic water, the remainder being that remaining in the body from prior dosages), that should give a concentration of ~1.71 μM, reducing infectivity by ~60% immediately after ingestion of 1 L of Indian tonic water, decreasing over the next 24 hours to ~.47 μM, with a reduced infectivity of ~40%, per [13].

    Given that no doctor is going to give you chloroquine or hydroxychloroquine as a prophylactic measure, using Indian tonic water containing quinine to reduce infectivity would seem to be a prudent preventative measure.

    [1] https://www.drugs.com/npp/quinine.html

    [2] https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1365-2710.2007.00788.x

    [3] https://blogs.sciencemag.org/pipeline/archives/2019/01/22/quinines-target

    [4] https://www.sciencedirect.com/science/article/pii/S0924857920300881

    [5] https://friendslab.com/quinine-use-and-detection/

    [6] https://www.drugbank.ca/drugs/DB00468

    [7] https://en.wikipedia.org/wiki/Tonic_water

    [8] https://en.wikipedia.org/wiki/Quinine

    [9] https://healthfully.com/287838-leg-cramps-magnesium-calcium.html

    [10] https://www.webmd.com/drugs/2/drug-19765/cal-mag-zinc-ii-oral/details/list-interaction-details/dmid-455/dmtitle-aluminum-and-magnesium-antacids-quinidine-quinine/intrtype-drug

    [11] https://academic.oup.com/jn/article/131/2/305/4687001

    [12] https://www.businessinsider.com/coronavirus-symptoms-loss-of-smell-taste-covid-19-anosmia-hyposmia-2020-3?op=1

    [13] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1232869/

    [14] https://www.nature.com/articles/s41422-020-0282-0

  5. Jeff Id said

    This study didnt’ work out at all:
    https://www.sciencedirect.com/science/article/pii/S0399077X20300858?via%3Dihub

  6. Jeff Id said

    This isn’t a study but appears better:
    https://nypost.com/2020/04/04/long-island-doctor-tries-new-hydroxychloroquine-for-covid-19-patients/

  7. Jeff Id said

    Chinese study – no paper:
    https://www.contagionlive.com/news/results-from-a-controlled-trial-of-hydroxychloroquine-for-covid19

  8. Jeff Id said

    Doctor reporting positive results
    https://abc7.com/health/la-doctor-seeing-success-with-hydroxychloroquine-to-treat-covid-19/6079864/

  9. Jeff Id said

    Congresswoman claiming she was saved by drug
    https://www.breitbart.com/the-media/2020/04/07/nolte-michigan-democrat-says-she-almost-didnt-receive-hydroxychloroquine-due-to-state-block/

  10. Jeff Id said

    96 year old saved
    https://www.foxnews.com/health/dr-marc-siegel-opens-up-about-his-father-96-and-his-use-of-hydroxychloroquine

  11. Jeff Id said

    NJ doc says it is working well
    https://www.northjersey.com/story/news/coronavirus/2020/04/07/hydroxychloroquine-coronavirus-nj-doctors-use-malaria-drug/2951640001/

  12. Jeff Id said

    china paper
    https://www.barrons.com/articles/hydroxychloroquine-trial-randomized-covid-19-efficacy-51585748653

  13. Jeff Id said

    http://thejewishvoice.com/2020/04/hydroxychloroquine-helps-90-year-old-musician-recover-as-dem-wants-trump-tried-with-crimes-against-humanity/

  14. Jeff Id said

    another anecdotal statement from France
    https://www.telegraph.co.uk/news/2020/04/09/controversial-french-virologist-claims-chloroquine-breakthrough/

  15. Jeff Id said

    French study expanded to 1000 patients. This is only the abstract but very positive news.

    Click to access Abstract_Raoult_EarlyTrtCovid19_09042020_vD1v.pdf

  16. Jeff Id said

    New paper on VA saying hydroxychloroquine alone caused more deaths and when combined with Azythromycin no effect.

    Click to access 2020.04.16.20065920v1.full.pdf

    It’s a terribly difficult paper to accept as medications were applied at different times and amounts. The study is non-random from the VA electronic records. The drugs may have been used only for the worst cases which would skew the entire thing and I can’t figure that out from the data as presented. Waiting until the virus is in the cells is not intended by any of the in-vitro or early human studies to be the preferred use. Of course the media is all over it. Statistical work is convoluted as well.

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